Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition
Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functio...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.733700/full |
| _version_ | 1819113565452238848 |
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| author | Arafat Siddiqui Manuela Tumiati Alia Joko Jouko Sandholm Pia Roering Sofia Aakko Reetta Vainionpää Katja Kaipio Kaisa Huhtinen Liisa Kauppi Johanna Tuomela Sakari Hietanen |
| author_facet | Arafat Siddiqui Manuela Tumiati Alia Joko Jouko Sandholm Pia Roering Sofia Aakko Reetta Vainionpää Katja Kaipio Kaisa Huhtinen Liisa Kauppi Johanna Tuomela Sakari Hietanen |
| author_sort | Arafat Siddiqui |
| collection | DOAJ |
| description | Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50–85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers. |
| first_indexed | 2024-12-22T04:31:25Z |
| format | Article |
| id | doaj.art-6a72803515b2449c90dd67582d36c593 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T04:31:25Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-6a72803515b2449c90dd67582d36c5932022-12-21T18:39:00ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-09-011110.3389/fonc.2021.733700733700Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl InhibitionArafat Siddiqui0Manuela Tumiati1Alia Joko2Jouko Sandholm3Pia Roering4Sofia Aakko5Reetta Vainionpää6Katja Kaipio7Kaisa Huhtinen8Liisa Kauppi9Johanna Tuomela10Sakari Hietanen11Institute of Biomedicine, University of Turku, Turku, FinlandONCOSYS, Research Programs Unit, University of Helsinki, Helsinki, FinlandDepartment of Biology, Åbo Akademi University, Turku, FinlandTurku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, FinlandInstitute of Biomedicine, University of Turku, Turku, FinlandInstitute of Biomedicine, University of Turku, Turku, FinlandLaboratory of Genetics, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, FinlandInstitute of Biomedicine, University of Turku, Turku, FinlandInstitute of Biomedicine, University of Turku, Turku, FinlandONCOSYS, Research Programs Unit, University of Helsinki, Helsinki, FinlandInstitute of Biomedicine, University of Turku, Turku, FinlandTurku University Hospital, FICAN West Cancer Centre, Turku, FinlandCritical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50–85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers.https://www.frontiersin.org/articles/10.3389/fonc.2021.733700/fullDNA repaircell cycle arrestc-Ablimatinibmitoxantrone |
| spellingShingle | Arafat Siddiqui Manuela Tumiati Alia Joko Jouko Sandholm Pia Roering Sofia Aakko Reetta Vainionpää Katja Kaipio Kaisa Huhtinen Liisa Kauppi Johanna Tuomela Sakari Hietanen Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition Frontiers in Oncology DNA repair cell cycle arrest c-Abl imatinib mitoxantrone |
| title | Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition |
| title_full | Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition |
| title_fullStr | Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition |
| title_full_unstemmed | Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition |
| title_short | Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition |
| title_sort | targeting dna homologous repair proficiency with concomitant topoisomerase ii and c abl inhibition |
| topic | DNA repair cell cycle arrest c-Abl imatinib mitoxantrone |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.733700/full |
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